D G Chapman1,2, E B Mougey3, J L Van der Velden4, K G Lahue4, M Aliyeva1, N Daphtary1, K L George3, S M Hoffman4, R W Schneider4, R P Tracy1,5, G S Worthen6, M E Poynter1, S P Peters7, J J Lima3, Y M W Janssen-Heininger4, C G Irvin1. 1. Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA. 2. Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 3. Nemours Pharmacogenetics Center, Nemours Children's Clinic, Jacksonville, FL, USA. 4. Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA. 5. Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA. 6. Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA. 7. Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Abstract
BACKGROUND: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. OBJECTIVE: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. METHODS: Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. RESULTS: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). CONCLUSIONS AND CLINICAL RELEVANCE: Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.
BACKGROUND: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. OBJECTIVE: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. METHODS:Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. RESULTS: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). CONCLUSIONS AND CLINICAL RELEVANCE: Our animal model and humanpatient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.
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